Project Summary In Vivo Optical Imaging of Alpha-Synuclein Aggregation Kevin Webb, J. Chris Rochet, and Jason Cannon, Purdue University This project entails the application of a high resolution whole brain optical molecular imaging method to determine the pathogenic mechanism involved in the temporal and spatial development of Parkinson's disease (PD). PD is a debilitating movement disorder af?icting 5 million people worldwide that imposes an economic burden of more than $14 billion each year in the United States alone. While the causes of most cases are unknown, environmental and genetic factors have been repeatedly linked to increased PD risk. Abnormal aggregation of the presynaptic protein alpha-synuclein (aSyn) is thought to play a key role in PD pathogenesis. Aggregation is postulated to occur at an early stage in the brain stem, and then in later stages in speci?c areas of the brain where neuronal loss or dysfunction results in the cardinal motor symptoms. Although the mechanism by which aSyn aggregation migrates throughout the brain is not well understood, there is evidence that cell secretion pathways are involved. We will optically image states of aSyn aggregation throughout the whole living brain at high spatial resolution and at different times of aSyn expression, presenting a basis for achieving critically needed understanding related to PD onset and progression. The approach will use our recent discovery of a method to form images with unprecedented spatial resolution from highly scattered light and our earlier discovery of how to image ?uorescence resonance energy transfer (FRET) in vivo. Completion of this project will enable us to extract critical insights into the time-course and extent of aSyn propagation throughout the brain, as well as the aggregation state of transmitted aSyn species, in a live animal model. Knowing the basis for progression of PD will provide opportunities for the development of early-stage treatment, before substantial brain damage occurs.